Obesity is among the leading risk factors for type 2 diabetes, a disease that primarily originates from insulin resistance in the liver, white adipose tissue, and skeletal muscle, compounded by insufficient insulin secretion from pancreatic β cells. White adipose tissue plays a central role in this process, as it has the capacity to alter its volume according to nutritional status. During energy excess, it expands to store the surplus, but this expansion can become dysfunctional and promote ectopic fat deposition in other tissues, metabolic dysregulation, and progressive insulin resistance. This expansion can occur through an increase in the number of adipocytes (hyperplasia) or through enlargement of pre-existing adipocytes via lipid accumulation (hypertrophy), the latter being associated with metabolic alterations such as glucose intolerance and hyperinsulinemia, independently of total fat mass. Nevertheless, the molecular events that predispose adipose tissue to hypertrophy remained poorly defined.
Here, the authors establish that adipocyte hypertrophy is triggered by the loss of the corepressor GPS2 (G protein pathway suppressor 2), a subunit of the HDAC3 corepressor complex, during obesity. Previous work by the team had already linked, in human adipose tissue, reduced GPS2 expression to increased inflammatory gene expression. To dissect this mechanism, the researchers used a mouse model lacking GPS2 specifically in adipocytes (GPS2 AKO), complemented by in vitro approaches on 3T3-L1 adipocytes and human adipose tissue explants, employing chromatin immunoprecipitation, oxygen consumption measurements, assessment of lipolysis under isoproterenol stimulation, and transcriptomic sequencing.
Under conditions of energy surplus, adipocyte GPS2 deficiency causes hypertrophy, inflammation, and mitochondrial dysfunction. This phenotype is driven by the activation of HIF1A (hypoxia-inducible factor 1-alpha), which orchestrates inadequate adipose tissue remodeling and disrupts mitochondrial activity. Notably, pharmacological or genetic inhibition of HIF1A reverses these alterations, establishing the causal nature of this pathway. Correlation analysis of gene expression profiles in human adipose tissue further reveals a negative relationship between GPS2 on the one hand, and HIF1A, adipocyte hypertrophy, and insulin resistance on the other, supporting the relevance of this mechanism in humans.
The authors therefore propose that obesity-associated loss of GPS2 in adipocytes predisposes to maladaptive expansion of white adipose tissue and to a pro-diabetic state, in both mice and humans.